Benzonitrile and benzothiocyano intermediates

ABSTRACT

There are described compounds of the formula ##STR1## in which R 1  is hydrogen or C 1-6  alkyl, R 2  is hydrogen, C 1-6  alkyl or C 3-6  alkenyl, X and Y are each oxygen, sulphur, sulphinyl or sulphonyl, n is 2 to 6 and Z is 1H-tetrazol-5-yl, 1H-tetrazol-5-ylthio, 1H-tetrazol-5-ylsulphinyl, 1H-tetrazol-5-ylsulphonyl, cyano or thiocyano, provided that when both X and Y are oxygen Z is 1H-tetrazol-5-ylthio, 1H-tetrazol-5-ylsulphinyl, 1H-tetrazol-5-ylsulphonyl or thiocyano; and salts thereof. The compounds in which Z is other than cyano or thiocyano have pharmaceutical activity and inhibit leukotriene action or formation. &#39;

This invention relates to novel compounds, pharmaceutical compositionscontaining them and their use as pharmaceuticals.

The compounds of the invention are of the formula ##STR2## in which R¹is hydrogen or C₁₋₆ alkyl, R² is hydrogen, C₁₋₆ alkyl or C₃₋₆ aklenyl, Xand Y are each oxygen, sulphur, sulphinyl or sulphonyl, n is 2 to 6 andZ is 1H-tetrazol-5-yl, 1H-tetrazol-5-ylthio, 1H-tetrazol-5-ylsulphinyl,1H-tetrazol-5-ylsulphonyl, cyano or thiocayano, provided that when bothX and Y are oxygen Z is 1H-tetrazol-5-ylthio, 1H-tetrazol-5-ylsulphinyl,1H-tetrazol-5-ylsulphonyl or thiocyano; and salts thereof.

Compounds of the aboce formula (I), with the exception of those in whichZ is cyano or thiocyano which are intermediates in the preparation ofthe remaining compounds, have useful pharmaceutical properties. They areindicated for use inter alia in the prophylactic and thereapeutictreatment of immediate hypersensitivity diseases included asthma and inthe alleviation of status asthmaticus.

A particular group of compounds according to formula (I) are those inwhich R¹ is hydrogen or C₁₋₆ alkyl, R² is hydrogen, C₁₋₆ alkyl or C₃₋₆alkenyl, X and Y are each oxygen or sulphur, n is 2 to 6, and Z is CN or1H-tetrazol-5-yl, provided that X and Y cannot both be oxygen.

A further group of compounds according to the invention are those offormula (I) in which R¹ is hydrogen or C₁₋₆ alkyl, R² is hydrogen, C₁₋₆alkyl or C₃₋₆ alkenyl, X and Y are each oxygen, suplur, sulphinyl orsulphonyl, n is 2 to 6 and Z is 1H-tetrazol-5-yl, 1H-tetrazol-5-ylthio,1H-tetrazol-5-ylsulphinyl, 1H-tetrazol-5-ylsulphonyl, cyano orthiocyano, provided that when X and Y are each oxygen or sulphur, Z is1H-tetrazol-5-ylthio, 1H-tetrazol-5-ylsulphinyl,1H-tetrazol-5-ylsulphonyl or thiocyano. Such compounds are preferablythose in which X and Y are each oxygen or sulphur and Z is1H-tetrazol-5-ylthio, 1H-tetrazol-5-ylsulphinyl,1H-tetrazol-5-ylsulphonyl or thiocyano.

In the above formula (I) reference to a "C₁₋₆ alkyl" group includes, forexampe, methly, ethyl, propyl, isopropyl and tert. butyl, and a "C₃₋₆alkenyl" group includes for example allyl, isopropenyl, butenyl,isobutenyl and 3-methyl-2-butenyl.

In the above formula (I) it is preferred that R¹ is C₁₋₆ alkyl. Thepreferred value of R² is C₁₋₆ alkyl and the preferred values of X areoxygen or sulphur and of Y sulphur. It is moreover preferred that nshould be 2 to 4. Thus an especially preferred group of pharmaceuticalcompounds according to the invention is of formula (I) in which R¹ isC₁₋₄ alkyl, R² is C₁₋₆ alkyl, X is oxygen or sulphur, Y is sulphur, n is2 or 3 And Z is 1H-tetrazol-5-yl or 1H-tetrazol-5-ylthio; andpharmaceutically acceptable salts thereof.

A particularly useful group of pharmaceutical compounds is of thefollowing formula ##STR3## in which R¹ is C₁₋₆ alkyl, R² is C₁₋₆ alkyl,n is 2 or 3; and pharmaceutically acceptable salts thereof. A furthergroup of especially useful compounds is of the formula ##STR4## whereR¹, R² and n have the above defined meanings; and pharmaceuticallyacceptable salts thereof.

When the compound of formula (I) bears a tetrazolyl, tetrazolylthio,tetrazolylsulphinyl or tetrazolylsulphonyl group, or the compound hassome other acidic substituent, base addition salts can be prepared andthese are regarded as part of the present invention. Examples of suchsalts are those derived from ammonium hydroxide and alkali and alkalineearth metal hydroxides, carbonates and bicarbonates, as well as saltsderived from aliphatic and aromatic amines, aliphatic diamines andhydroxy alkylamines. Bases especially useful in the preparation of suchsalts include ammonium hydroxide, potassium carbonate, sodiumbicarbonate, calcium hydroxide, methylamine, diethylamine, ethylenediamine, cyclohexylamine and ethanolamine. The potassium and sodium saltforms are particularly preferred.

Apart from pharmacuetically acceptable addition salts, other salts arealso included within the scope of the invention such as, for example,those with picric or oxalic acid, since they may serve as intermediatesin the purification of compounds or in the preparation of otherpharmaceutically acceptable salts, or they may be useful foridentification, characterization or purification of the free compound.

The pharmaceutical compounds of the invention can be prepared by aprocess which comprises reacting a compound of formula (1) in which Z isCN or SCN with an azide, optionally followed when X and/or Y issulphinyl or sulphonyl or Z is tetrazolylsulphinyl ortetrazolylsulphonyl, by oxidation.

The process of the invention is preferably carried out in an organicsolvent such as a polar aprotic solvent for example dimethyl formamideand suitably at a temperature in the range of from 25° C. to 150° C. Theazide employed can be, for example, an alkali metal azide and we havefound that a combination of alkali metal azide, for example sodiumazide, and ammonium chloride is especially convenient.

When it is desired to convert a sulphur atom in the resulting compoundto a sulphinyl group: ##STR5## one of the conventional reagents for suchpurpose can be employed and a mild oxidising agent such as hydrogenperoxide in methanol or alkali metal periodate in aqueous alcohol isespecially convenient, the reaction generally being carried out at atemperature of from 25° C. to the reflux temperature of the reactionmixture. In the case of compounds in which there is a sulphonyl group:##STR6## a stronger oxidising agent must be employed such as for examplehydrogen peroxide in acetic acid or metachloroperbenzoic acid inmethanol, the reaction being performed at a temperature of from 25° C.to 100° C.

Compounds of formula (I) in which Z is CN or SCN can be prepared bycondensing a compound of formula ##STR7## with a compound of formula##STR8## in which R¹ and R² have the values defined above, Z is CN orSCN, and one of A and B is OH or SH and the other is --X(CH₂)_(n) X',where X' is a leaving group.

Thus, for example, the cyano and thiocyano intermediate compounds inwhich X is oxygen and Y is sulphur can for example be prepared accordingto the following reaction ##STR9## where R¹, R² and n have their abovedefined meanings, Z is CN or SCN and X' is a leaving group such as, forexample, halogen especially bromine or chlorine. Such a reaction can becarried out in an inert organic solvent in the presence of a base suchas for example sodium hydride in dimethyl formamide or anhydrous sodiumcarbonate and methyl ethyl ketone, and preferably at an elevatedtemperature such as for example from 50° C. to the reflux temperature.

Compounds of formula (IV) are known compounds or can be prepared fromknown compounds by methods well-known in the art. Compounds of formula(V) can be prepared, for example, from 4-cyanophenol by a series ofreactions involving first the preparation of 4-mercaptobenzonitrile byreaction of the phenol with dialkylthiocarbamoyl halide to give the0-substituted-N,N-diethylthiocarbamate which on heating with zincrearranges to provide the corresponding S-substituted compound.Treatment with base at elevated temperatures gives the4-mercaptobenzonitrile. The sequence of reactions can be illustrated forthe preparation of 4-mercaptobenzonitrile as follows: ##STR10## Theresulting 4-mercapto-benzonitrile can then be reacted with theappropriate reagent of formula X'(CH₂)_(n) X" where X" is a leavinggroup such as for example a halogen atom, as follows: ##STR11##

When it is desired to prepare cyano or thiocyano intermediate compoundsin which X and Y in formula (I) are both oxygen or sulphur, or in whichX is sulphur and Y is oxygen, similar preparative techniques may beemployed to those described above.

The compounds of the present invention are pharmacologically active,being inhibitors of leukotriene action as shown by the following tests:(a) the in vitro test on guinea pig ileum segments at concentrations offrom 10 ng to 50 μg, according to the method of Schild, 1947 Brit. J.Pharm. 2,197-206 (the pharmacological compounds of the followingExamples exhibited an IC₅₀ against LTD4 of less than 10⁻⁴ molar); (b)the in vivo Guinea Pig Pulmonary Function Test of Austen and Drazen 1974J. Clin. Invest. 53:1679-1685 at intravenous dosage levels of from 0.05μg to 5.0 mg/kg; and (c) a modified "Herxheimer" test at doses of from25 to 200 mg/kg. The "Herxheimer" test is based on an allergicbronchospasm induced in guinea pigs and which closely resembles anasthmatic attack in man. The mediators causing the bronchospasm are verysimilar to those released when sensitised human lung tissue ischallenged with an antigen. In the modified test employed in respect ofcompounds of the present invention, the animals were pretreated with ahistamine antagonist, mepyramine, at a dose of 0.5 mg/kg i.p., 30minutes before challenge. This modification masks the histamine effectto reveal better the leukotriene effect. The compounds also inhibit theformation of leukotrienes as indicated by their action in the testdescribed by Harvey and Osborne Journal of Pharmacological Methods 9,147-155 (1983).

The compounds are accordingly indicated for therapeutic use in thetreatment of diseases in which leukotrienes are implicated. Theseinclude immediate hypersensitivity diseases, allergic reactions of thepulmonary system in which leukotrienes are thought to be causalmediators of bronchospasm, for example, in allergic lung disorders suchas extrinsic asthma and industrial asthmas such as Farmers lung andPigeon Fanciers lung, and in other inflammatory disorders, for example,associated with acute or chronic infectious diseases such as allergicskin diseases, ectopic and atopic eczemas, psoriasis, contacthypersensitivity and angioneurotic oedema, bronchitis and cysticfibrosis and rheumatic fever.

The compounds may be administered by various routes, for example, by theoral or rectal route, by inhalation, topically or parenterally, forexample by injection, being usually employed in the form of apharmaceutical composition. Such compositions form part of the presentinvention and are prepared in a manner well known in the pharmaceuticalart and normally comprise at least one active compound in associationwith a pharmaceutically acceptable diluent or carrier. In making thecompositions of the present invention, the active ingredient willusually be mixed with a carrier, or diluted by a carrier, and/orenclosed within a carrier which may, for example, be in the form of acapsule, sachet, paper or other container. Where the carrier serves as adiluent, it may be a solid, semi-solid, or liquid material which acts asa vehicle, excipient or medium for the active ingredient. Thus, thecomposition may be in the form of tablets, lozenges, sachets, cachets,elixirs, suspensions, aerosols as a solid or in a liquid medium,ointments containing for example up to 10% by weight of the activecompound, soft and hard gelatin capsules, suppositories, injectionsolutions and suspensions and sterile packaged powders. Foradministration by inhalation, particular forms of presentation includeaerosols, atomisers and vaporisers.

Some examples of suitable carriers are lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, syrup, methyl cellulose, methyl- and propyl-hydroxybenzoate, talc, magnesium stearate and mineral oil. Thecompositions of the invention may, as is well known in the art, beformulated so as to provide quick, sustained or delayed release of theactive ingredient after administration to the patient.

Where the compositions are formulated in unit dosage form, it ispreferred that each unit dosage form contains from 5 mg to 500 mg, moreusually 25 to 200 mg, of the active ingredient. The term "unit dosageform" refers to physically discrete units suitable as unit dosages forhuman subjects and animals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier.

The active compounds are effective over a wide dosage range and forexample dosages per day will normally fall within the range of 0.5 to300 mg/kg. and in the treatment of adult humans, more usually in therange of from 5 to 100 mg/kg. However it will be understood that theamount of the compound actually administered will be determined by aphysician, in the light of the relevant circumstances including thecondition to be treated, the choice of compound to be administered andthe chosen route of administration and therefore the above dosage rangesare not intended to limit the scope of the invention in any way.

The following Examples illustrate the invention.

EXAMPLE 1 (i) 0-(4-Cyanophenyl)-N,N-dimethylthiocarbamate

A mixture of 4-cyanophenol (59.5 g) potassium carbonate (75.9 g),dimethylthiocarbamoyl chloride (72.9 g) and dry acetone (1 liter) wasstirred at room temperature for two hours, then refluxed for 16 hours(see Newman and Karnes J.O.C. 31 3980 (1966)).

The reaction mixture was cooled, poured into water (3 liters) andstirred vigorously for 30 minutes. The solid material was collected byfiltration, washed with water on the sinter, and dried in vacuo to givethe product as an off white solid, melting point 122°-123° C.

(ii) S-(4-Cyanophenyl)-N,N-dimethylthiocarbamate

The product from (i) (51.0 g) was heated with zinc wool (4.0 g) under anitrogen stream at 220° C. for 3 hours.

The crude product was recrystallised (CCl_(4/) hexane) to give purewhite needles, melting point 110° C.

(iii) 4-Mercaptobenzonitrile

The product from (ii) (35.3 g) was refluxed with a 4% ethanolicpotassium hydroxide solution (720 ml) for two hours.

The ethanol was evaporated off, the residue suspended in water andacidified with 2 molar hydrochloric acid. The resulting precipitate wascollected by filtration and dried to give the title compound as ayellowish solid, melting point about 60° C.

(iv) 3-(4-Cyanophenylthio)-1-chloropropane

To a refluxing suspension of 4-mercaptobenzonitrile (10.00 g), potassiumcarbonate (30.67 g) and dry acetone (100 ml) was added1-bromo-3-chloropropane (11.67 g) and refluxing was continued forfurther three hours. At this stage an additional amount (6 g) ofbromochloropropane was added, then refluxing was continued for a further16 hours.

The reaction mixture was evaporated in vacuo, the residue stirred withwater (100 ml), then extracted with dichloromethane (2×100 ml); theextracts were dried and evaporated to give a yellow oil. The crude oilwas distilled on a Vigreux column and the fraction of boiling point 160°C/0.4 mmHg collected to yield the product as a colourless oil, whichcrystallised on standing.

(v) 4-[3-(4-Acetyl-3-hydroxy-2-propylohenoxy)propylthio]-benzonitrile.

To a suspension of benzene-washed 50% sodium hydride (0.57 g) in drydimethylformamide (50 ml) was added 2,4-dihydroxy-3-propyl-acetophenone(4.56 g) and sodium iodide (3.55 g), and the mixture stirred at 50° C.for 20 minutes. A solution of 3-(4-cyanophenylthio)-1-chloropropane(5.00 g) in dry dimethylformamide (15 ml) was then added dropwise, andthe reaction mixture heated and stirred at 100° C. for four hours.

The reaction mixture was cooled, the dimethylformamide evaporated invacuo, the residue stirred with water (100 ml) and extracted withdichloromethane (2×100 ml). The combined extracts were washed with 25%sodium carbonate solution (2×150 ml) and water (2×200 ml), dried (MgSO₄)and evaporated to give the product as a brown oil which rapidlycrystallised, melting point 100° C.

(vi) 1-{2-Hydroxy-3-propyl-4-[3-(4-(1H-tetrazol-5-yl)phenylthio)propoxy]phenyl}ethanone.

To a solution of the benzonitrile (prepared as in (v) above) (6.7 g) indry dimethylformamide (60 ml) was added sodium azide (2.96 g) andammonium chloride (2.44 g) and the suspension was heated at 120° C. fortwo hours. A further amount cf sodium azide (1.2 g) and ammoniumchloride (1.0 g) was then added and heating was continued for a furthertwo hours.

The reaction mixture was cooled, stirred with water (600 ml), and thefiltered material dried in vacuo and finally recrystallised fromethanol/water (with charcoal decolourisation) to give the title compoundas a beige solid, melting point 160°-162° C.

The following compounds were prepared in a similar manner

4-[2-(4-Acetyl-3-hydroxy-2-propylphenoxy)ethylthio]benzonitrile, meltingpoint 114°-116° C.

1-{2-Hydroxy-3-propyl-4-[2-(4-(1H-tetrazol-5-yl)phenylthio)ethoxy]phenyl}ethanone,melting point 167°-169° C.

EXAMPLE 2 (i) 2-Hydroxy-3-propyl-4-thioacetophenone

The above compound was prepared as described in Example 1 following thesteps (i), (ii) and (iii) using 2,4-hydroxy-3-propylacetophenone asstarting material, melting point 70°-72° C.

(ii) 2-Hydroxy-3-propyl-4-(3-chloropropylthio)acetophenone.

The above compound was prepared as described in Example 1 (iv) using theproduct of (i) above. The resulting compound was a liquid, boiling point205° C./0.05 mm mercury.

(iii) 4-[3-(4-Acetyl-3-hydroxy-2-propylphenylthio)propoxy]-benzonitrile

This compound was prepared as described in Example 1(v) using4-cyanophenol and the product of (ii) above, melting point 90°-92° C.

(iv)1-{2-Hydroxy-3-propyl-4-[3-(4-(1H-tetrazol-5-yl)phenoxy)propylthio]phenyl}ethanone.

This compound was prepared as described in Example 1(vi) using thebenzonitrile of (iii) above as substrate, melting point 178°-182° C.

The following compounds were prepared in a similar manner4-[2-(4-Acetyl-3-hydroxy-2-propylphenylthio)ethoxy]benzonitrile, meltingpoint 102°-104° C.1-{2-Hydroxy-3-propyl-4-[2-(4-(1H-tetrazol-5-yl)phenoxy)ethylthio]phenyl}ethanone,melting point 172°-175° C.

EXAMPLE 3 (i)4-[3-(4-Acetyl-3-hydroxy-2-propylphenylthio)propylthiobenzonitrile

This compound was prepared by the method of Example 1(v) but using2-hydroxy-3-propyl-4-thioacetophenone, melting point about 80° C.

(ii)1-{2-Hydroxy-3propyl-4-[3-(4-(1H-tetrazol-5-yl)phenylthio)propylthio]phenyl}ethanone

This compound was prepared by the method of Example 1(vi) using thebenzonitrile from (i) above as substrate, melting point 160°-162° C.

EXAMPLE 41-{2-Hydroxy-3-propyl-4-[3-(4-(1H-tetrazol-5-yl)phenylsulphinyl)propoxy]phenyl}ethanone

1-{2-Hydroxy-3-propyl-4-[3-(4-(1H-tetrazol-5-yl)phenylthio)propoxy]phenyl}ethanone (0.412 g) was dissolved in methanol (20 ml) and20% aqueous hydrogen peroxide (0.7 ml) added. The resulting solution wasrefluxed for 36 hours (see Drabowicz and Mikozajczyk Synth. Comm. 11(12) 1025 to 1030 (1981)).

Water (20 ml) was added, the methanol evaporated in vacuo, the remainingaqueous phase extracted with ethyl acetate (2×20 ml); the combinedorganic extracts were dried with magnesium sulphate and evaporated invacuo to give a pale yellow solid which was recrystallised fromethanol/water (with decolourising charcoal) to give the productsulphoxide as fluffy white crystals, melting point 130° C., withdecomposition.

The following compound was prepared in a similar manner

1-{2-Hydroxy-3-propyl-4-[2-(4-(1H-tetrazol-5-yl)phenylsulphinyl)ethoxy]phenyl}ethanone,melting point 128°-130° C.

EXAMPLE 51-{2-Hydroxy-3-propyl-4-[3-(4-(1H-tetrazol-5-yl)phenylsulphonyl)propoxy]phenyl}ethanone.

1-{2-Hydroxy-3-propyl-4-[3-(4-(1H-tetrazol-5-yl)phenylthiopropoxy]pheny}ethanone(0.412 g) was dissolved in glacial acetic acid (6 ml) and 20% aqueoushydrogen peroxide (1 ml) was added to the mixture. The resultingsolution was heated at 60° C for 24 hours.

The reaction mixture was cooled, poured into water (75 ml) and stirredvigorously for 30 minutes. The flocculent precipitate was collected byfiltration, dried in vacuo and finally recrystallised from ethanol/water(with decolourising charcoal) to give the required sulphone as a whitesolid, melting point 120° C.

The following compounds were prepared in a similar manner

1-{2-Hydroxy-3-propyl-4-[3-(4-(1H-tetrazol-5-yl)phenoxy)propylsulphonyl]phenyl}ethanone,melting point 168°-172° C.

1-{2-Hydroxy-3-propyl-4-[2-(4-(1H-tetrazol-5-yl)phenylsulphonyl)ethoxy]phenyl}ethanone,melting point 197°-199° C.

EXAMPLE 61-{2-Hydroxy-3-propyl-4-[3-(4-thiocyanophenoxy)propoxy]phenyl}ethanone

A mixture of 4(3-chloropropoxy)-2-hydroxy-3-propylacetophenone (4.06 g)4-thiocyanophenol (JACS Vol. 78 p 858) (2.25 g), sodium iodide (2.25 g),and anhydrous sodium carbonate (6 g) was boiled and stirred under refluxin methyl ethyl ketone (60 ml, anhydrous) for 80 hours. The solvent wasevaporated and the residual mass stirred with water (100 ml) anddichloromethane (100 ml). The organic layer was separated and theaqueous layer extracted a second time with dichloromethane (100 ml). Thetwo organic layers were combined, washed with water and dried overanhydrous magnesium sulphate. After evaporation there remained 5.0 g ofa yellow gum which slowly crystallized. This was recrystallized fromether/light petrol ether to give 3.2 g white solid, melting point 85° C.

The following compound was similarly prepared

1-{2-Hydroxy-3-propyl-4-[2-(4-thiocyanophenoxy)ethoxy]phenyl}ethanone,melting point 86° C.

EXAMPLE 71-{2-Hydroxy-3-propyl-4-[3-(4-(1H-tetrazol-5-ylthio)phenoxy)propoxy]lphenyl}ethanone

A mixture of1-{2-hydroxy-3-propyl-4-[3-(4-thiocyanophenoxy)propoxy]phenyl}ethanone(7.7 g), sodium azide (3.9 g) and ammonium chloride (3.2 g) dissolved inanhydrous dimethylformamide (40 ml) was stirred and heated at 115° C.for 4 hours.

The mixture was poured into 200 ml ice/water and the pH adjusted to 3.0with N hydrochloric acid, resulting in a yellow precipitate. This wascollected, washed with water, and dissolved in 2N NaOH solution (80 ml).This solution was extracted twice with 40 ml ether and the organiclayers discarded. The aqueous layer was acidified with 5N hydrochloricacid, resulting in a sticky solid precipitate. After crystallizationfrom aqueous methanol there was obtained 5.9 g of a pale yellow solid,melting point 114° C.

The following compound was similarly prepared.

1-{2-Hydroxy-3-propyl-4-[2-(4-(1H-tetrazol-5-ylthio)phenoxy)ethoxy]phenyl}ethanone,melting point 160° C.

EXAMPLE 81-{2-Hydroxy-3-propyl-4-[2(1H-tetrazol-5-ylsulphonyl)phenoxy)ethoxy]phenyl}ethanone

1-{2-Hydroxy-3-propyl-4-[2-(4-(1H-tetrazol-5-ylthio)phenoxy)ethoxy]phenyl}ethanone(1.85 g), was dissolved in 30 ml glacial acetic acid. Hydrogen peroxide(100 vol, 5 ml) was added and the mixture stirred and heated at 70° C.for 6 hours. The solvent was evaporated off under vacuum and the residuetriturated with water to give a solid. After recrystallization fromether/light petroleum there was obtained 1.02 g of white product,melting point 100°-102° C.

The following compound was similarly prepared

1-{2-Hydroxy-3-propyl-4-[3-(4-(1H-tetrazol-5-ylsulphonylphenoxy)propoxy]phenyl}ethanone, melting point 88°-90° C.

The following formulations are prepared from pharmaceutical compoundsaccording to the invention as described in the above Examples

EXAMPLE 9

    ______________________________________                                        Aerosol                                                                       ______________________________________                                        Active Ingredient     100    mg                                               Ethanol               30     ml                                               Propellent 12/114     q.s.                                                    ______________________________________                                    

The active ingredient is dissolved in ethanol, filled into glassbottles, sealed with a valve (metered to 0.05 ml) and charged with themixed propellants.

EXAMPLE 10

    ______________________________________                                        Tablet                                                                        ______________________________________                                        Active ingredient    100 mg                                                   Dried starch         400 mg                                                   Polyvinyl pyrrolidone                                                                              50 mg                                                    Sodium carboxymethyl starch                                                                        50 mg                                                    Stearic acid         20 mg                                                    ______________________________________                                    

The active ingredient and starch are mixed together and massed with asolution of polyvinyl pyrrolidone in alcohol. The mass is extrudedthrough a screen, dried, sized and mixed with sodium carboxymethylstarch and stearic acid prior to compression on a tablet machine.Tablets weighing 620 mg are obtained.

EXAMPLE 11

    ______________________________________                                        Capsules                                                                      ______________________________________                                        Active ingredient                                                                               50 mg                                                       Starch flowable  300 mg                                                       Silicone fluid    5 mg                                                        ______________________________________                                    

A portion of the starch is mixed with the silicone fluid. To the powderis added the active ingredient and the remainder of the starch. Thisblended mixture is filled into hard gelatin capsules.

What we claim is:
 1. A compound of the formula ##STR12## in which R¹ ishydrogen or C₁₋₆ alkyl, R² is hydrogen, C₁₋₆ alkyl or C₃₋₆ alkenyl, Xand Y are each oxygen, sulphur, sulphinyl or sulphonyl, n is 2 to 6 andz is cyano or thiocyano provided that when X and Y are oxygen z isthiocyano.
 2. A compound according to claim 1 in which R¹ is C₁₋₆ alkyl,R² is C₁₋₆ alkyl, X is oxygen or sulphur, Y is sulphur, and n is 2 or 3.3. A compound according to claim 2 in which R¹ is C₁₋₆ alkyl, R² is C₁₋₆alkyl, X is oxygen, Y is sulphur, and n is 2 or
 3. 4. The compound ofclaim 3 which is4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio]benzonitrile.